The primary objective of this mentored career development award in clinical research is for the candidate Dr. Jeffrey Greenberg to acquire the skills and expertise to become an independent investigator in clinical and translational arthritis research. Under the direction of Drs. Steven Abramson and Harry Ostrer, the candidate has constructed a focused training program that will build upon the candidate's prior Masters of Public Health degree in epidemiology and health services research. Selected courses with direct relevance to the current research proposal and anticipated future research directions will include intensive coursework in human genetics and translational research. The didactic component of the training program will also include weekly seminars, regular face-to-face mentor meetings and participation in Dr. Abramson's weekly arthritis laboratory meetings. In addition, this career development program will benefit from the oversight of a carefully selected Advisory Committee of senior research scientists with expertise in clinical and translational research. The research for this proposal will be conducted at three participating sites of the Consortium of Rheumatology Researchers of North America (CORRONA) including NYU, Johns Hopkins and Albany. This prospective cohort study will investigate single nucleotide polymorphisms (SNPs) of candidate inflammatory mediator genes as prognostic biomarkers for RA patients. The three specific aims include: 1) To determine whether genetic biomarkers can predict response to targeted biologic response modifiers;2) To determine whether genetic biomarkers can predict clinical disease activity and radiographic severity;and 3) To determine whether genetic biomarkers can predict the risk of serious infection. Candidate genes will be assessed using high-density single nucleotide polymorphism (SNP) genotyping to facilitate linkage disequilibrium (LD) mapping and extended haplotype construction. Clinical trials of BRM agents indicate that up to one-third of RA patients do not achieve a clinical response, and serious adverse outcomes including infections can occur. Pharmacogenetic studies that can identify genetic biomarkers to "personalize" the likelihood of clinical response to targeted BRMs, as well as the risk of adverse outcomes, will represent a major advance for the treatment of RA.